The present invention relates to a process for commercially, inexpensively, and also simply producing 5-fluorouracil by a direct fluorination reaction of uracil.
5-fluorouracil, itself is used in large quantities as an anti-tumor and it is also used as a synthetic intermediate for producing other anti-tumors.
Therefore, there is a need for a simple and inexpensive process for producing 5-fluorouracil commercially.
Heretofore, among the processes for producing 5-fluorouracil, a method in which uracil is subjected in a particular medium to a direct fluorination reaction by elemental fluorine has been considered as a relatively advantageous one and thus many processes for improving the direct fluorination of uracil have been proposed. None of these improved process, however, can be said to be satisfactory because of their economics and complexity.
Elemental fluorine has an extremely strong reactivity, i.e. oxidation power, and if uracil is directly exposed to fluorine, ignition or explosion may occur. Thus it is necessary to create a process capable of fluorinating commercially with high economics at the desired position only of uracil, while controlling this violent reaction.
Heretofore, a process in which uracil is reacted in water with elemental fluorine diluted with an inert gas has been used for achieving such a purpose. This process has the decisive drawback that if the process is tried to carry out in good yield in achieving the aimed reaction, a prohibitively low concentration of uracil in water must be employed, thus leading to a lower step efficiency, on the other hand, if better efficiency is aimed at, a polyfluorinated by-product such as 5,5-difluoro-6-hydroxy-6-hydrouracil is produced with the remaining unreacted uracil, thus adversely affecting the product purity, which is one of the most important requirements of a medication. For solving the problem set forth above, a number of processes have been proposed in which, the following solvents are used; (1) acetic acid (Japanese Patent Publication No. 50-25476), (2) trifluoroacetic acid (Japanese Laid Open Patent Application No. 51-149287), (3) an aqueous solution of formic acid (Japanese Laid Open Patent Application No. 55-81818), (4) a concentrated aqueous solution of hydrofluoric acid (Japanese Laid Open Patent Application No. 52-13394), and (5) a mixed solution of hydrogen fluoride and an aliphatic carboxylic acid (Japanese Laid Open Patent Application No. 53-59681).
However, all of these processes are difficult to perform safely on an industrial scale. Acetic acid, formic acid, and an aliphatic carboxylic acid suffer from the drawbacks that they may possibly react with elemental fluorine, thus causing ignition or explosion depending upon the control of the process, and they also are disadvantageous with respect to safety and economics because of the need to use large amounts. On the other hand, hydrogen fluoride and a concentrated aqueous solution of hydrofluoric acid are highly toxic, and their use in large quantities is accompanied by danger.
Trifluoroacetic acid is expensive and thus is economically disadvantageous, even though no danger of explosion exists.
In general, a process for producing 5-fluorouracil starting from uracil and elemental fluorine comprises two steps consisting of a step of reacting uracil with elemental fluorine and a step of thermally treating the resultant intermediate. In the conventional processes, uracil and elemental fluorine is reacted in a particular medium in the first step, and the medium is distilled off from the resultant reaction solution under heating in the second step.
Such distilling off, however, consumes considerable energy. Therefore, an economic and simple process has been desired. In this regard, a process wherein uracil is slurried in a concentrated aqueous solution of hydrosilicofluoric acid and is reacted with elemental fluorine to form a precipitate which is filtered off and the precipitate thus obtained is subjected to high temperature thermal treatment (Japanese Laid Open Patent Application No. 59-16880) offers a prima facie solution of the aforementioned drawbacks.
The process, however, poses the problems that it requires high temperature thermal treatment, that the material for constructing the reaction vessel is limited due to the requirement of resisting highly corrosive hydrosilicofluoric acid, and that cost of the hydrosilicofluoric acid is relatively high.
In addition, due to regulations concerning environmental pollution and waste water the disposal of hydrosilicofluoric acid is a difficult problem. Thus, this method is not truly satisfactory from a commercial viewpoint. Moreover, it is an important matter of public health to cope with the problems stemming from hydrogen fluoride produced as a by-product from a reaction between elemental fluorine and uracil. Heretofore, there has been no means provided for economically solving this problem.
The present inventors have performed numerous studies aimed at solving the following three problems listed below:
(1) selection of a reaction solvent which is commercially available and inexpensive, which is non-inflammable when in contact with elemental fluorine and makes it possible to proceed the fluorination reaction with high efficiency and also which is an absorbent for hydrogen fluoride gas.
(2) the selection of a reaction solvent which has extremely low solubility for the final product, 5-fluorouracil, but an adequate solubility for the intermediate product resulting from the reaction between uracil and elemental fluorine. In other words, a reaction solvent should be selected such that the reaction between uracil and elemental fluorine can proceed smoothly by dissolving the intermediate resulting from said reaction, while allowing the precipitation of the final product, 5-fluorouracil, from the reaction medium after thermal treatment of the intermediate, the precipitation making it possible to effect the separation of the final product, 5-fluorouracil, with ease.
(3) selection of a reaction solvent which has no deleterious effect on the thermal treatment of an intermediate resulting from the reaction between uracil and elemental fluorine and permits the conversion of the intermediate to the final product, 5-fluorouracil, at a relatively low temperature.
As a result of the studies set forth above, the present inventors found that an aqueous phosphoric acid solution satisfies all of the three requirements set forth and were led to the present invention.